Block copolymers of acrylates and methacrylates with fluoroalkenes

ABSTRACT

A block copolymer comprising a fluorinated block and a non-fluorinated block and method of making the block copolymer are provided. Also provided herein are a coating on an implantable device comprising the block copolymer and method of using the implantable device.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation application of U.S. application Ser. No.10/714,111, filed on Nov. 14, 2003, the teaching of which isincorporated hereto by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention generally relates to fluorinated and nonfluorinated blockcopolymer and composition formed therefrom useful for coating animplantable device such as a drug eluting stent.

2. Description of the Background

Blood vessel occlusions are commonly treated by mechanically enhancingblood flow in the affected vessels, such as by employing a stent. Stentsare used not only for mechanical intervention but also as vehicles forproviding biological therapy. To effect a controlled delivery of anactive agent in stent medication, the stent can be coated with abiocompatible polymeric coating. The biocompatible polymeric coating canfunction either as a permeable layer or a carrier to allow a controlleddelivery of the agent.

Fluorinated polymers, such as poly(vinylidenefluoride-co-hexafluoropropylene), have been used to form drug-elutingstent (DES) coatings and can effectively control the release ofpharmaceutical agents from a stent. DES coatings formed of thesefluorinated polymers also have excellent mechanical properties and arebiocompatible and biologically inert. However, polymers of fluorinatedolefins are very hydrophobic and may have low glass transitiontemperatures. Too high a hydrophobicity of the polymeric coating on aDES often reduces the permeability of the coating and thus slows downthe release rate of a drug on the coating to an undesirable level.

The polymer and methods of making the polymer disclosed herein addressthe above described problems.

SUMMARY OF THE INVENTION

Disclosed herein is a fluorinated block copolymer comprising afluorinated block and a non-fluorinated block. The non-fluorinated blockof the polymer provides improved vascular responses and/or improvedpermeability for controlled release of pharmaceutical agents.

In accordance with one aspect of the invention, the non-fluorinatedblock comprises a polyolefinic block of the following structure:

wherein R₁ is —CH₃, —CF₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, -phenylnaphthyl, —COOR₃, or —CONR₃R₄;

wherein R₂ is —H, —CH₃, —CF₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,-phenyl, or naphthalenyl; and

wherein R₃ and R₄ are —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,—CH₂CH₂OH, or —PEG.

In another embodiment, the fluorinated block can be, for example, ablock of poly(fluorinated olefins), for example, a block having thefollowing structure:

In a further embodiment, the fluorinated block copolymer has a structureas shown below:

wherein R₁ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂OH, or—PEG; and

wherein R₂ is —H, —CH₃, —CF₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,-phenyl, or naphthyl.

The polymer can form a coating composition for coating an implantabledevice and/or a coating formed thereof for controlling the release rateof a bioactive agent. The block copolymer can be formed by polymerizinga non-fluorinated olefin such as acrylate, methacrylate, or styrene inthe presence of a copper catalyst, such as an ATRP (atom transferradical polymerization) catalyst (see, for example, Matyjaszewski, K.Controlled Radical Polymerization; American Chemical Society:Washington, D.C., 1998; Vol. 685; Honigfort, M. E.; Brittain, W. J.;Bosanac, T.; Wilcox, C. S. Polym. Prepr. 2002, 43, 561), and afluorinated di-halo macromer.

The fluorinated block copolymer can be used to form a coatingcomposition comprising the fluorinated block copolymer alone or incombination with another material or polymer, optionally with abioactive agent. The coating composition thus formed can be coated ontoan implantable device such as a DES. The release rate of the bioactiveagent on the DES can be controlled by fine-tuning the hydrophobicity ofthe fluorinated block copolymer using a hydrophilic group such asethylene glycol or polyethylene glycol.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 is a scheme for making a block copolymer having non-fluorinatedblocks bearing a hydrophilic ethylene glycol pendent groups.

DETAILED DESCRIPTION

A block copolymer comprising a fluorinated block and a non-fluorinatedblock and method of making the block copolymer are provided. Alsoprovided herein are a coating on an implantable device comprising theblock copolymer and optionally a bioactive agent and method of using theimplantable device.

Fluorinated Block Copolymer

A block of non-fluorinated polymer can be incorporated into afluorinated polyolefin to form a block copolymer comprising anon-fluorinated block and a fluorinated block. The non-fluorinated blockprovides the polymer with improved vascular responses and/or improvedpermeability which are desirable for controlled release of a bioactiveagent.

Fluorinated Blocks

In accordance with one aspect of the invention, the fluorinated blockcopolymer can be synthesized via a fluorinated macromer where at leastone of the two termini of the macromer is functionalized. In oneembodiment, the termini of the fluorinated macromer are functionalizedwith two halo groups which can be two of chloro, bromo, iodo or acombination thereof. For example, the two halo groups can be two iodogroups. The functionalized fluorinated macromer then can be used as amacro-initiator to form a block copolymer with non-fluorinated monomers.The term fluorinated macromer refers to a poly(fluoroolefin). As usedherein, the term poly(fluoroolefin) is used inter-exchangeably with theterm poly(fluoroalkene).

In an embodiment, the di-halo fluorinated macromer can be apoly(fluorinated olefin) bearing two halogen groups at both termini.This dihalo fluorinated macromer can be readily synthesized bypolymerizing a fluorinated olefin or a mixture of a fluorinated olefinin the presence of a dihalide and a peroxide (Ying, et al., Polym.Preprints 39(2):843 (1998); Zhang, et al., Polymer 40:1341 (1999); andModena, et al., J. fluorine Chem. 4315(1989)). For example, a diiodofluorinated macromer having as repeating unit —CF₂CH₂CF₂CF(CF₃)— can bereadily synthesized by polymerizing a mixture of vinylidene fluoride and1,1,2,3,3,3-hexafluoropropene in the presence of a peroxide and1,2-diiodo-1,1,2,2-tetrafluoroehthane (Scheme 1) (Ying, et al., Polym.Preprints 39(2):843 (1998); Zhang, et al., Polymer 40:1341 (1999); andModena, et al., J. fluorine Chem. 43 15 (1989)).

Non-Fluorinated Blocks

Materials or polymers useful as the non-fluorinated blocks describedherein include any polymers or macromers that can be directly attachedto a fluorinated macromer described herein or polymers or macromers thatcan be functionalized to attach one or more functional groups such ashydroxyl, amino, halo, and carboxyl and other linking groups. Exemplarymaterials or polymers useful as the non-fluorinated blocks include, butare not limited to, polyolefins, polyalkylene oxides, polyglycols suchas poly(ethylene glycol) and poly(propylene glycol), polylactic acid,poly(lactide-co-glycolide), polyhydroxyalkanoate,poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride,poly(glycolic acid-co-trimethylene carbonate), polyphosphoester,polyphosphoester urethane, poly(amino acids), poly(cyanoacrylates),poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-esters)(e.g. PEO/PLA), polyalkylene oxalates, polyphosphazenes, biomolecules,such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronicacid, polyurethanes, silicones, polyesters, polyolefins, polyisobutyleneand ethylene-alphaolefin copolymers, acrylic polymers and copolymers,vinyl halide polymers and copolymers, such as polyvinyl chloride,polyvinyl ethers, such as polyvinyl methyl ether, polyvinylidenehalides, such as polyvinylidene fluoride and polyvinylidene chloride,polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics, such aspolystyrene, polyvinyl esters, such as polyvinyl acetate, copolymers ofvinyl monomers with each other and olefins, such as ethylene-methylmethacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins,and ethylene-vinyl acetate copolymers, polyamides, such as Nylon 66 andpolycaprolactam, alkyd resins, polycarbonates, polyoxymethylenes,polyimides, polyethers, epoxy resins, polyurethanes, rayon,rayon-triacetate, cellulose acetate, cellulose butyrate, celluloseacetate butyrate, cellophane, cellulose nitrate, cellulose propionate,cellulose ethers, and carboxymethyl cellulose. As used herein, the term“non-fluorinated block” may include fluorinated pendant groups such as—CF₃.

In another embodiment, the non-fluorinated block can be incorporatedinto the fluorinated block by polymerizing an unsaturated compound, forexample, acrylate or methacrylate using a catalyst such as a coppercatalyst in the presence of a di-halo fluorinated macromer. For example,a block copolymer with a perfluorinated block can be made from monomersincluding vinylidene fluoride, hexafluoroprop ylene,tetrafluoroethylene, and other fluorinated olefins in the presence of afluorinated dihalide under conditions of a standard radicalpolymerization (Ying et al., 1998; Zhang et al., 1999; and Modena etal., 1989, supra) to form a fluorinated di-halo macromer which canundergo polymerization with an unsaturated compound via an ATRPcatalyst, as shown in Scheme 2 (Perrier, et al., Tetrahedron Lett 584053 (2002); Jo, et al., Polym Bull (Berlin) 44:1 (2002)).

The fluorinated di-halo macromer can be used to attach the macromer tomany other types of polymers. For example, the di-halo groups can bereplaced by many functional groups, for example, functional groupsbearing a negative or partially negative charge. This allows theformation of a block copolymer bearing a poly(fluorinated olefin) blockand one or two blocks of other nature such as polyesters, polyethers,polyanhydrides, polyglycols, poly(alkylene oxides),polyhydroxyalkanoates, polyphosphazenes, polyurethanes, or otherbiocompatible polymers commonly used in the art of drug delivery. Thefluorinated di-halo macromer can form into a metallo macromer, which maybe useful for linking the macromer with another biocompatible block orpolymer.

As shown in Scheme 2, many different polymers can be made. For example,in addition to variations of the substituents such as R₁ and R₂ inScheme 2, the ratio of the fluorinated block to the non-fluorinatedblock can be varied, leading to formation of block copolymers havingdifferent level of hydrophobicity and permeability with differentsurface and mechanical properties. For example, following the methodshown in Scheme 2, block copolymers comprising a fluorinated block andnon-fluorinated blocks of hydrophilic monomers such as hydroxyethylmethacrylate, hydrpxypropyl methacrylate, N-vinyl pyrrolidone, orpolyethylene glycol acrylate can be synthesized. The monomers withlabile hydroxy functionalities can be protected with a protecting group(Pg), which can be cleaved at the completion of the reaction (FIG. 1).The protecting group can be, for example, t-butyl-dimethylsilane ortrimethylsilane which can then be deprotected in stochiometric yieldswith acidic hydrolysis.

In one embodiment, the block copolymer described herein has afluorinated block having the following structure:

and a non-fluorinated block has the following structure

wherein R₁ can be —CH₃, —CF₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,-phenyl, naphthyl, —COOR₃, or —CONR₃R₄;

wherein R₂ can be —H, —CH₃, —CF₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,-phenyl, or naphthalenyl; and

wherein R₃ and R₄ can be —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,—CH₂CH₂OH, or —PEG.

In another embodiment, the block copolymer has a formula of thefollowing structure:

wherein R₁ can be —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂OH,or —PEG, and

wherein R₂ can be —H or —CH₃, —CF₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,-phenyl or naphthyl.

In a further embodiment, the block copolymer has a formula of thefollowing structure:

wherein R₁ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂OH, or—PEG, and

wherein R₂ is —H or —CH₃.

In still a further embodiment, the block copolymer described herein hasa fluorinated block having the following structure:

and a non-fluorinated block that can be polyesters, polyethers,polyanhydrides, polyglycols, poly(alkylene oxides),polyhydroxyalkanoates, polyphosphazenes, polyurethanes, or a combinationthereof.

Compositions of Fluorinated Block Copolymers

The fluorinated block copolymer described above can be used to formcoating compositions for coating an implantable device, for example, astent. The fluorinated block copolymer can be used alone or incombination with another polymer. For use as DES coatings, thecomposition can include a bioactive agent.

Bioactive Agents

The bioactive agent can be any agent that is biologically active, forexample, a therapeutic, prophylactic, or diagnostic agent. Examples ofsuitable therapeutic and prophylactic agents include synthetic inorganicand organic compounds, proteins and peptides, polysaccharides and othersugars, lipids, and DNA and RNA nucleic acid sequences havingtherapeutic, prophylactic or diagnostic activities. Nucleic acidsequences include genes, antisense molecules which bind to complementaryDNA to inhibit transcription, and ribozymes. Compounds with a wide rangeof molecular weight can be encapsulated, for example, between 100 and500,000 grams or more per mole. Examples of suitable materials includeproteins such as antibodies, receptor ligands, and enzymes, peptidessuch as adhesion peptides, saccharides and polysaccharides, syntheticorganic or inorganic drugs, and nucleic acids. Examples of materialswhich can be encapsulated include enzymes, blood clotting factors,inhibitors or clot dissolving agents such as streptokinase and tissueplasminogen activator, antigens for immunization, hormones and growthfactors, polysaccharides such as heparin, oligonucleotides such asantisense oligonucleotides and ribozymes and retroviral vectors for usein gene therapy. Representative diagnostic agents are agents detectableby x-ray, fluorescence, magnetic resonance imaging, radioactivity,ultrasound, computer tomagraphy (CT) and positron emission tomagraphy(PET). Ultrasound diagnostic agents are typically a gas such as air,oxygen or perfluorocarbons.

In the case of controlled release, a wide range of different bioactiveagents can be incorporated into a controlled release device. Theseinclude hydrophobic, hydrophilic, and high molecular weightmacromolecules such as proteins. The bioactive compound can beincorporated into polymeric coating in a percent loading of between0.01% and 70% by weight, more preferably between 1% and 35%% by weight.

In one embodiment, the bioactive agent can be for inhibiting theactivity of vascular smooth muscle cells. More specifically, thebioactive agent can be aimed at inhibiting abnormal or inappropriatemigration and/or proliferation of smooth muscle cells for the inhibitionof restenosis. For example, the bioactive agent can be for enhancingwound healing in a vascular site or improving the structural and elasticproperties of the vascular site. Examples of active agents also includeantiproliferative substances such as actinomycin D, or derivatives andanalogs thereof (manufactured by Sigma-Aldrich 1001 West Saint PaulAvenue, Milwaukee, Wis. 53233, or COSMEGEN available from Merck).Synonyms of actinomycin D include dactinomycin, actinomycin IV,actinomycin I₁, actinomycin X₁, and actinomycin C₁. The bioactive agentcan also fall under the genus of antineoplastic, anti-inflammatory,antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic,antibiotic, antiallergic and antioxidant substances. Examples of suchantineoplastics and/or antimitotics include paclitaxel (e.g. TAXOL® byBristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g. Taxotere®,from Aventis S.A., Frankfurt, Germany) methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax ä (Biogen, Inc., Cambridge, Mass.). Examplesof such cytostatic or antiproliferative agents include angiopeptin,angiotensin converting enzyme inhibitors such as captopril (e.g.Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.),cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co.,Inc., Whitehouse Station, N.J.), calcium channel blockers (such asnifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand nameMevacor® from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonalantibodies (such as those specific for Platelet-Derived Growth Factor(PDGF) receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), andnitric oxide. An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which may beappropriate include alpha-interferon, genetically engineered epithelialcells, tacrolimus, dexamethasone, and rapamycin and structuralderivatives or functional analogs thereof, such as40-O-(2-hydroxy)ethyl-rapamycin (known as Everolimus, available fromNovartis as Certican™), 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapaamycin, and40-O-tetrazole-rapamycin. The foregoing substances are listed by way ofexample and are not meant to be limiting. Other active agents which arecurrently available or that may be developed in the future are equallyapplicable.

The dosage or concentration of the bioactive agent required to produce afavorable therapeutic effect should be less than the level at which thebioactive agent produces toxic effects and greater than the level atwhich non-therapeutic results are obtained. The dosage or concentrationof the bioactive agent required to inhibit the desired cellular activityof the vascular region can depend upon factors such as the particularcircumstances of the patient, the nature of the trauma, the nature ofthe therapy desired, the time over which the ingredient administeredresides at the vascular site, and if other active agents are employed,the nature and type of the substance or combination of substances.Therapeutic effective dosages can be determined empirically, for exampleby infusing vessels from suitable animal model systems and usingimmunohistochemical, fluorescent or electron microscopy methods todetect the agent and its effects, or by conducting suitable in vitrostudies. Standard pharmacological test procedures to determine dosagesare understood by one of ordinary skill in the art.

Methods of Using the Coating Composition

The coating composition can be coated onto any implantable device by anyestablished coating process, e.g., a spray process. Generally, thecoating process involves dissolving or suspending the composition in asolvent to form a solution or a suspension of the coating composition,and then applying the solution or suspension to an implantable devicesuch as a stent.

As used herein, an implantable device may be any suitable medicalsubstrate that can be implanted in a human or veterinary patient. Aexemplary implantable device is a stent such as DES. Examples of stentsinclude self-expandable stents, balloon-expandable stents, andstent-grafts. Other exemplary implantable devices include grafts (e.g.,aortic grafts), artificial heart valves, cerebrospinal fluid shunts,pacemaker electrodes, and endocardial leads (e.g., FINELINE and ENDOTAK,available from Guidant Corporation, Santa Clara, Calif.). The underlyingstructure of the device can be of virtually any design. The device canbe made of a metallic material or an alloy such as, but not limited to,cobalt chromium alloy (ELGILOY), stainless steel (316L), high nitrogenstainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, “MP35N,”“MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from Standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Devices made frombioabsorbable or biostable polymers could also be used with theembodiments of the present invention.

The implantable device described herein can be used to treat any medicalcondition, for example, a vascular disorder in an animal such as ahuman. Representative medical conditions that can be treated using theimplantable device described herein include, but are not limited to,cancer, restenosis, vulnerable plaque, thrombosis or inflammation.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. An implantable device comprising a coating which comprises a blockcopolymer, the block copolymer comprising a fluorinated block and atleast one non-fluorinated block, wherein the fluorinated block is apoly(fluoroalkene).
 2. The implantable device of claim 1, wherein thefluorinated block has repeating units of the following structure:

wherein the non-fluorinated block has repeating units of the followingstructure:

wherein R₁ is selected from the group consisting of —CH₃, —CF₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, -phenyl, naphthyl, —COOR₃, and —CONR₃R₄;wherein R₂ is selected from the group consisting of —H, —CH₃, —CF₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, -phenyl, and naphthyl; and whereinR₃ and R₄ are selected from the group consisting of —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂OH, and —PEG.
 3. The implantabledevice of claim 2, wherein the block copolymer has a formula comprisingthree blocks, the middle block having repeating units of the followingstructure:

and the two end blocks having repeating units of the following structure

wherein R₁ is selected from the group consisting of —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂OH, and —PEG, and wherein R₂ isselected from the group consisting of —H or —CH₃, —CF₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, -phenyl and naphthyl.
 4. The implantabledevice of claim 3 wherein RI is selected from the group consisting of—CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂OH, and —PEG, andwherein R₂ is —H or —CH₃.
 5. The implantable device of claim 1, whereinthe fluorinated block has repeating units of the following structure:

wherein the non-fluorinated block is a polymer selected from the groupconsisting of polyesters, polyethers, polyanhydrides, polyglycols,poly(alkylene oxides), polyhydroxyalkanoates, polyphosphazenes,polyurethanes, and a combination thereof.
 6. The implantable device ofclaim 1, which is a drug-eluting stent, wherein the coating furthercomprises a bioactive agent.
 7. The implantable device of claim 2, whichis a drug-eluting stent, wherein the coating further comprises abioactive agent.
 8. The implantable device of claim 3, which is adrug-eluting stent, wherein the coating further comprises a bioactiveagent.
 9. The implantable device of claim 4, which is a drug-elutingstent, wherein the coating further comprises a bioactive agent.
 10. Theimplantable device of claim 5, which is a drug-eluting stent, whereinthe coating further comprises a bioactive agent.
 11. The implantabledevice of claim 6, wherein the bioactive agent is selected from thegroup consisting of tacrolimus, dexamethasone, rapamycin, everolimus,40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.12. The implantable device of claim 7, wherein the bioactive agent isselected from the group consisting of tacrolimus, dexamethasone,rapamycin, everolimus, 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.13. The implantable device of claim 8, wherein the bioactive agent isselected from the group consisting of tacrolimus, dexamethasone,rapamycin, everolimus, 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.14. The implantable device of claim 9, wherein the bioactive agent isselected from the group consisting of tacrolimus, dexamethasone,rapamycin, everolimus, 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.15. The implantable device of claim 10, wherein the bioactive agent isselected from the group consisting of tacrolimus, dexamethasone,rapamycin, everolimus, 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.16. A method of treating restenosis or vulnerable plaque, comprisingimplanting in a human being in need thereof the implantable device ofclaim
 1. 17. A method of treating restenosis or vulnerable plaque,comprising implanting in a human being in need thereof the implantabledevice of claim
 2. 18. A method of treating restenosis or vulnerableplaque, comprising implanting in a human being in need thereof theimplantable device of claim
 11. 19. A method of treating restenosis orvulnerable plaque, comprising implanting in a human being in needthereof the implantable device of claim
 12. 20. A method of treatingrestenosis or vulnerable plaque, comprising implanting in a human beingin need thereof the implantable device of claim 13.